Pharmaceutical compounds originally developed for human use have also been used in veterinary medicine. However, the effectiveness of human drugs in non-human animals is unpredictable because of metabolic differences between humans and the various non-human animal species. Even for individuals within a species, the effectiveness of a particular drug can be highly variable. For example, H1-receptor antagonists such as clemastine have been used as antihistamines for both humans and animals. However, doses which are effective in humans have been found to be ineffective in canine and equine subjects because of poor oral bioavailability and rapid elimination of the clemastine (see Hansson et al., Veterinary Dermatology 2004, 15, pages 152-158; and Törneke et al., J. Vet. Pharmacol. Therap. 26, pages 151-157, 2003). Therapeutic plasma levels of clemastine in canine and equine subjects were only obtained by intravenous administration using relatively high (compared to human) doses, which severely limit the utility of clemastine for veterinary applications.
It is known that certain biologically active compounds are better absorbed through the oral mucosa than through other routes of administration, such as through the stomach or intestine. However, formulations suitable for such administration through the oral mucosa present their own problems. For example, the biologically active compound must be compatible with the other components of the composition such as propellants, solvents, etc. Many such formulations have been proposed. For example, U.S. Pat. No. 4,689,233 to Dvorsky et al., describes a soft gelatin capsule for the administration of the anti-coronary drug nifedipine dissolved in a mixture of polyether alcohols. U.S. Pat. No. 4,755,389 to Jones et al., describes a hard gelatin chewable capsule containing nifedipine. A chewable gelatin capsule containing a solution or dispersion of a drug is described in U.S. Pat. No. 4,935,243 to Borkan et al. U.S. Pat. No. 4,919,919 to Aouda et al., and U.S. Pat. No. 5,370,862 to Klokkers-Bethke, describe a nitroglycerin spray for administration to the oral mucosa comprising nitroglycerin, ethanol, and other components. An orally administered pump spray is described by Cholcha in U.S. Pat. No. 5,186,925. Aerosol compositions containing a hydrocarbon propellant and a drug for administration to a mucosal surface are described in U.K. 2,082,457 to Su, U.S. Pat. No. 3,155,574 to Silson et al., U.S. Pat. No. 5,011,678 to Wang et al., and by Parnell in U.S. Pat. No. 5,128,132. It should be noted that these references discuss bioavailability of solutions by inhalation rather than through the membranes to which they are administered. Each of the above-identified references is incorporated herein by reference in its entirety.
Transmucosal absorption through the oral mucosal surfaces allows permeation of pharmaceuticals such as nutrients or drugs directly into the bloodstream and then into the cells within a matter of minutes. Within the oral cavity, a number of mucosal surfaces may be used to deliver pharmaceuticals, including but not limited to: (i) sublingual surfaces, i.e., the mucosal membranes lining the floor of the mouth, (ii) buccal surfaces, i.e., the mucosal membranes lining the cheeks, (iii) lingual surfaces, i.e., the surface membranes of the tongue, (iv) palatal surfaces, i.e., the membranes lining the roof of the mouth, (v) pharyngeal surfaces, i.e., the membranes of the pharynx, (vi) gingival mucosa, i.e., the gums, and (vii) gingival sulcus, i.e., the cavity formed between the teeth and gums. Conventional oral delivery of a drug via ingestion is often not easily accomplished for various reasons such as difficulty that an owner may have in obliging their animal to swallow a tablet or liquid, inability to handle an animal that dislikes the taste of the medication and resists being treated, and medical conditions that make it difficult for animals to take oral formulations. In animals, these limitations are often exacerbated because the animal is unaware that the treatment is intended to improve the animal's physical condition.
It is well known to animal owners and veterinarians alike that oral administration of a drug to an animal has its associated drawbacks (e.g., difficulty stimulating swallowing, the animal spewing out the pill, or failing to receive proper dosage). In addition, conventional oral administration of drugs to animals has disadvantages, such as hepatic first pass metabolism and enzymatic degradation within the gastrointestinal tract, that prohibit administration of certain classes of drugs, especially peptides and proteins. Although intravenous administration may overcome these drawbacks, the invasiveness to the animal, difficulties for the animal owner, as well as increased costs and risks of infection, make intravenous administration a less viable alternative.
The oral mucosa offers an attractive route of transmucosal administration for systemic drug delivery to animals. For example, an oral spray having a non-toxic aerosol pump can deliver a drug directly into the bloodstream. When sprayed into the mouth, micro-sized droplets are immediately absorbed through the mucosal lining into the capillaries, which lie close to the surface of the lining in the mouth. This process can provide for definitive absorption of the drug within a short time span without causing any extra stress to the organs.
Film delivery systems for use on mucosal surfaces are also known. These types of systems, which are water-insoluble and usually in the form of laminated, extruded or composite films, are described in U.S. Pat. Nos. 4,517,173; 4,572,832; 4,713,243; 4,900,554; and 5,137,729, which are incorporated herein by reference in their entirety. U.S. Pat. No. 4,517,173 describes and claims a membrane-adhering film consisting of at least three layers, including a pharmaceutical layer, a poorly water soluble layer, and an intermediate layer. The pharmaceutical layer includes the drug and a cellulose derivative selected from hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose. The poorly water soluble layer is made by the combination of one or more cellulose derivatives with a poorly water soluble fatty acid, and the intermediate layer is made of cellulose derivatives. U.S. Pat. No. 4,572,832 relates to a soft film for buccal delivery, made by the combined use of a water soluble protein, a polyol, and a polyhydric alcohol such as cellulose and polysaccharides, and also teaches the use of coloring or flavoring agents. U.S. Pat. No. 4,713,243 describes a single or multi-layered bioadhesive thin film made from 40-95% water soluble hydroxypropyl cellulose, 5-60% water-insoluble ethylene oxide, 0-10% water-insoluble ethyl cellulose, propyl cellulose, polyethylene, or polypropylene, and a medicament. The films are three-layered laminates and include a bioadhesive layer, a reservoir layer, and a non water-soluble outer protective layer. U.S. Pat. No. 4,900,554 teaches a soft adhesive film applicable to the oral mucosa containing a systemic drug and comprising a mixture of a vinyl acetate non-water-soluble homopolymer, an acrylic acid polymer, and a cellulose derivative. Finally, U.S. Pat. No. 5,137,729 describes a device for use in the oral cavity having an adhesive layer including a mixture of an acrylic acid polymer, a water-insoluble cellulose derivative, and a pharmaceutical preparation, and a water-insoluble, or sparingly soluble, backing layer. The adhesive layer contains the pharmaceutical and, upon application to the mucosal surface, delivers the drug.
Recently it has been demonstrated that buccal administration of active agents can result in absorption of active agents through the oral mucosa. For example, U.S. Pat. Nos. 5,869,082; 5,955,098; 6,110,486; and 6,676,931, each of which is incorporated by reference in its entirety for all purposes, disclose administration of active agents using a buccal aerosol spray or capsule. In addition, Published U.S. Patent Application Nos. 2005/0025717, 2005/0025716, 2005/0025715, 2005/0025714, 2005/0025713, 2005/0025712, 2005/0002867, 2004/0265239, 2004/0141923, 2004/0136915, 2004/0136914, 2004/0136913, 2004/0120896, 2004/0120895, 2004/0062716, 2003/0211047, 2003/0190286, 2003/0185761, 2003/0095927, 2003/0095926, 2003/0095925, 2003/0082107, 2003/0077229, 2003/0077228, 2003/0077227, and 2003/0039680, each of which is incorporated herein by reference in its entirety, disclose buccal aerosol sprays or capsules using polar and non-polar solvents, which provide biologically active agents for absorption through the oral mucosa.
However, the bioavailability of drugs administered using an aerosol or spray, e.g., to the respiratory system, can depend significantly on the particular formulation used, and even aerosol formulations which provide satisfactory bioavailability of the drug can exhibit undesirable side-effects such as irritation of the mucosal tissue.